Sue Ann Costa Clemens, Lily Weckx, Ralf Clemens, Ana Verena Almeida Mendes, Alessandra Ramos Souza, Mariana B V Silveira, Suzete Nascimento Farias da Guarda, Maristela Miyamoto de Nobrega, Maria Isabel de Moraes Pinto, Isabela G S Gonzalez, Natalia Salvador, Marilia Miranda Franco, Renata Navis de Avila Mendonça, Isabelle Silva Queiroz Oliveira, Bruno Solano de Freitas Souza, Mayara Fraga, Parvinder Aley, Sagida Bibi, Liberty Cantrell, Wanwisa Dejnirattisai, Xinxue Liu, Juthathip Mongkolsapaya, Piyada Supasa, Gavin R Screaton, Teresa Lambe, Merryn Voysey, Andrew J Pollard, Mustapha Bittaye, Danielle Woods, Sophie Davies, Holly Smith, Marta Ulaszewska, Helen Sanders, Reece Mabette, Sophie Vernon, Zara Valliji, Gracie Mead, Chitra Tejpal, Juyeon Park, Amy Beveridge, Ahmed Eldawi, Sally Felle, Thaiane Muniz Martins, Claudia Loureiro Martins Medrado, Laiana Januse de Arruda Cordeiro Matos, and team, RHH-001 study
Introduction The inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac, Sinovac) has been widely used in a two-dose schedule. We assessed whether a third dose of the homologous or a different vaccine could boost immune responses. Methods RHH-001 is a phase 4, participant masked, two centre, safety and immunogenicity study of Brazilian adults (18 years and older) in São Paulo or Salvador who had received two doses of CoronaVac 6 months previously. The third heterologous dose was of either a recombinant adenoviral vectored vaccine (Ad26.COV2-S, Janssen), an mRNA vaccine (BNT162b2, Pfizer–BioNTech), or a recombinant adenoviral-vectored ChAdOx1 nCoV-19 vaccine (AZD1222, AstraZeneca), compared with a third homologous dose of CoronaVac. Participants were randomly assigned (5:6:5:5) by a RedCAP computer randomisation system stratified by site, age group (18–60 years or 61 years and over), and day of randomisation, with a block size of 42. The primary outcome was non-inferiority of anti-spike IgG antibodies 28 days after the booster dose in the heterologous boost groups compared with homologous regimen, using a non-inferiority margin for the geometric mean ratio (heterologous vs homologous) of 0·67. Secondary outcomes included neutralising antibody titres at day 28, local and systemic reactogenicity profiles, adverse events, and serious adverse events. This study was registered with Registro Brasileiro de Ensaios Clínicos, number RBR–9nn3scw. Findings Between Aug 16, and Sept 1, 2021, 1240 participants were randomly assigned to one of the four groups, of whom 1239 were vaccinated and 1205 were eligible for inclusion in the primary analysis. Antibody concentrations were low before administration of a booster dose with detectable neutralising antibodies of 20·4% (95% CI 12·8–30·1) in adults aged 18–60 years and 8·9% (4·2–16·2) in adults 61 years or older. From baseline to day 28 after the booster vaccine, all groups had a substantial rise in IgG antibody concentrations: the geometric fold-rise was 77 (95% CI 67–88) for Ad26.COV2-S, 152 (134–173) for BNT162b2, 90 (77–104) for ChAdOx1 nCoV-19, and 12 (11–14) for CoronaVac. All heterologous regimens had anti-spike IgG responses at day 28 that were superior to homologous booster responses: geometric mean ratios (heterologous vs homologous) were 6·7 (95% CI 5·8–7·7) for Ad26.COV2-S, 13·4 (11·6–15·3) for BNT162b2, and 7·0 (6·1–8·1) for ChAdOx1 nCoV-19. All heterologous boost regimens induced high concentrations of pseudovirus neutralising antibodies. At day 28, all groups except for the homologous boost in the older adults reached 100% seropositivity: geometric mean ratios (heterologous vs homologous) were 8·7 (95% CI 5·9–12·9) for Ad26.COV2-S vaccine, 21·5 (14·5–31·9) for BNT162b2, and 10·6 (7·2–15·6) for ChAdOx1 nCoV-19. Live virus neutralising antibodies were also boosted against delta (B.1.617.2) and omicron variants (B.1.1.529). There were five serious adverse events. Three of which were considered possibly related to the vaccine received: one in the BNT162b2 group and two in the Ad26.COV2-S group. All participants recovered and were discharged home. Interpretation Antibody concentrations were low at 6 months after previous immunisation with two doses of CoronaVac. However, all four vaccines administered as a third dose induced a significant increase in binding and neutralising antibodies, which could improve protection against infection. Heterologous boosting resulted in more robust immune responses than homologous boosting and might enhance protection. Funding Ministry of Health, Brazil.